In conducting the proposed research we will continue to study the intrinsic ultrafiltration characteristics of isolated mammalian glomeruli in order to achieve a better understanding of the mechanisms which determine glomerular filtration in normal and pathologic states. During the past three years, we developed techniques for isolating intact glomeruli and inducing filtration in vitro, estimating filtration rate, ultrafiltration coefficient (LpA), glomerular cell and extracellular volume, glomerular compliance and resistance to perfusion. We have measured LpA of glomeruli of normal rats, rabbits, dog, sheep and humans. We have documented that LpA increases with increasing glomerular size in each species and decreases during volume depletion and in established ischemic and toxic injury. We will continue to refine our methods for estimating LpA by varying incubation conditions, oncotic agents and gradients used to produce filtration. We will study correlations between glomerular cell and basement membrane morphology and filtration and attempt to define the effects of alterations in total area of endothelial cell fenestrae, basement membrane and epithelial slit diaphragms. We will investigate the effects of vasoactive substances and their antagonists on glomerular function using agents administered in vivo or added to the incubation in vitro. We will also extend our studies to include glomeruli from normal human kidneys and renal biopsy specimens. We anticipate that these studies will lead to a better understanding of the process of glomerular filtration and the mechanisms by which it is modulated. This understanding may later permit rational intervention in human renal insufficiency.